Alterations of kynurenine pathway in alcohol use disorder and abstinence: a link with gut microbiota, peripheral inflammation and psychological symptoms

Sophie Leclercq,Philippe De Timary,Markus Schwarz,Nathalie M Delzenne,Peter Stärkel

doi:10.1038/s41398-021-01610-5

Abstract

The gut-brain communication is mostly driven by the immune, metabolic and neural pathways which remained poorly explored in patients with alcohol use disorder (AUD). The metabolites arising from the tryptophan-kynurenine pathway have gained considerable attention since they are at the interface between intestinal bacteria, host immune response and brain functions. This study described the circulating levels of kynurenine metabolites in AUD patients, at the onset (T1) and end (T2) of a 3-week detoxification program, and tested correlations between those metabolites and inflammatory markers, the gut microbiota and the psychological symptoms. Increased concentration of the neurotoxic metabolite quinolinic acid (QUIN) and decreased levels of the neuroprotector metabolite kynurenic acid (KYNA) which both modulate glutamatergic neurotransmission were observed in AUD patients, particularly at T2. The inflammatory marker hsCRP was associated with several metabolic ratios of the kynurenine pathway. Tryptophan, KYNA and QUIN were correlated with depression, alcohol craving and reaction time, respectively. Analysis of gut microbiota revealed that bacteria known as short-chain fatty acid producers, as well as bacterial metabolites including butyrate and medium-chain fatty acids were associated with some metabolites of the tryptophan-kynurenine pathway. Targeting the glutamatergic neurotransmission through the modulation of the kynurenine pathway, by manipulating the gut microbiota, might represent an interesting alternative for modulating alcohol-related behavior.

Highlights

Alcohol use disorder (AUD) is a psychiatric disease associated with leaky gut and alterations of the gut microbiota [1, 2]
Among the potentially circulating neuroactive metabolites, those arising from tryptophan metabolism have gained considerable attention since they are at the interface between intestinal bacteria, host immune response and brain functions [6]
alcohol use disorder (AUD) is associated with lower level of neuroprotective kynurenic acid (KYNA) and higher level of neurotoxic quinolinic acid (QUIN) The biological and psychological features of AUD patients and precision of 3.9%, and inter-day precision of 7.5%)

Summary

Introduction

Alcohol use disorder (AUD) is a psychiatric disease associated with leaky gut and alterations of the gut microbiota [1, 2]. Numerous experimental and clinical studies have highlighted a link between intestinal bacteria and the presence of emotional and cognitive symptoms in multiple neurological and psychiatric conditions [3]. Animal studies have shed light on the complex mechanisms underlying gut-brain interactions which mainly include metabolic, immune and vagus nerve-dependent pathways. Those communication pathways remain poorly studied in clinical populations. The metabolic component of the gut-brain communication pathway has never been explored in AUD patients. Among the potentially circulating neuroactive metabolites, those arising from tryptophan metabolism have gained considerable attention since they are at the interface between intestinal bacteria, host immune response and brain functions [6]

Methods

Results

Conclusion